Читать книгу Transporters and Drug-Metabolizing Enzymes in Drug Toxicity - Albert P. Li - Страница 14

The following are the events likely to occur with an orally administered drug.

Enteric events: An orally administered drug undergoes the following events:

1 Metabolism by intestinal microflora.

2 Entry into enterocytes via diffusion or transporter‐mediated uptake.

3 Metabolism by drug‐metabolizing enzymes in the enterocytes.

4 Efflux to the intestinal lumen via efflux transporters.

5 Entry of the drug and its metabolites into the portal circulation.

Hepatic events: Upon entry of a drug and its enteric metabolites into the portal circulation, the following events occur:

1 Entry into hepatocytes via diffusion or transporter‐mediated uptake.

2 Metabolism by drug‐metabolizing enzymes in the hepatocytes.

3 Excretion of parent drug and/or metabolites to the intestine as bile via diffusion or efflux transporters followed by excretion into the feces or reentry into the portal circulation (enterohepatic recirculation) via diffusion or uptake transporters.

4 Entry into the systemic circulation.

Extrahepatic events: Upon entry of a drug and its hepatic metabolites into the systemic circulation, the following events occur:

1 Entry into extrahepatic target cells via diffusion or transporter‐mediated uptake.

2 Metabolism by drug‐metabolizing enzymes in the target cells.

3 Exit of parent drug and/or metabolites from the target cells to the systemic circulation.

4 Excretion via urinary, perspiratory, respiratory pathways.

The manifestation of toxicity of the drug in question, either due to the parent molecule or its metabolites, is dependent on the concentration of the toxic moiety at the ultimate target. Metabolism (metabolic clearance, activation, and detoxification), uptake transport, and efflux transport can play critical roles on whether the toxic moiety will reach the critical concentration leading to the onset of toxicity.